Equine animals, e.g. horses, are affected by various metabolic disorders, including insulin resistance and hyperinsulinaemia. Insulin-related disorders are correlated or may be associated with a number of further equine disorders, conditions or syndromes, including impaired glucose tolerance, dyslipidaemia, dysadipokinaemia, obesity and/or regional adiposity, subclinical inflammation or systemic inflammation, in particular low grade systemic inflammation, which also comprises adipose tissue, Equine Metabolic Syndrome (EMS) and/or Equine Pituitary Pars Intermedia Dysfunction (PPID), also known as equine Cushing's syndrome. Both, EMS and PPID are characterized e.g. by laminitis, vascular dysfunction, hypertension, hepatic lipidosis, hyperadrenocorticism and/or atherosclerosis.
Such metabolic disorders in equine animals, for example, are only rarely associated with diabetes mellitus and hyperglycaemia as it is in humans or various other mammals.
In particular, insulin resistance in equine animals may be associated with EMS and/or PPID or may cause the development or progression of PPID. EMS and/or PPID may become manifest e.g. in laminitis. This devastating worldwide cause of mortality in horses is a multifactorial condition causing structural and mechanical changes in the supporting tissues within the hoof, resulting in acute and chronic pain, lameness, and potentially euthanasia. Equine laminae are highly metabolically active, and a complex microvascular bed is present. A significant body of evidence exists also for vascular dysfunction (endothelial cell dysfunction) during equine laminitis (Katz & Bailey, 2012). In vitro studies in equine digital vessels have shown insulin resistance-mediated endothelial and/or vascular dysfunction (Venugopal et al., 2011). A direct link between hyperinsulinaemia and laminitis has been documented in naturally-occurring forms of the disease (Treiber et al., 2006). However, the mechanism by which insulin resistance and/or hyperinsulinaemia cause EMS and/or PPID, in particular vascular dysfunction and/or laminitis in horses is poorly understood.
No satisfactory treatment is currently available for metabolic disorders such as insulin resistance, hyperinsulinaemia and associated disorders in equine animals, such as EMS and/or in case they are associated with or secondary to e.g. PPID, which become manifest e.g. by laminitis, vascular dysfunction, hypertension in equine animals. For instance, the use of Metformin is controversially discussed (Tinworth et al., 2012). Similarly, various treatment options are contemplated in equine PPID: dopamine receptor agonists (pergolide and bromocriptine), cortisol inhibitors (trilostane) and also serotonin antagonists (cyproheptidine) have been used (McGowan, 2005). But the effects of these treatments on insulin resistance and/or hyperinsulinaemia are controversial or seem to be hardly detectable e.g. with pergolide (Gehlen, 2014). In general high plasma insulin levels (unaffected by treatment) are associated with a poor outcome in horses suffering from equine PPID (McGowan, 2004).
In human medicine, insulin resistance, e.g. when manifest as diabetes mellitus type 2, is a well-recognised condition, and may lead in particular to hyperglycaemia (pathologically increased plasma glucose levels). Several oral antihyperglycaemic drugs are approved for human diabetes. These drugs act, e.g. by stimulating pancreatic insulin secretion in a glucose-independent or glucose-dependent manner (sulfonylurea/meglitinides or DPP IV inhibitors, respectively), by enhancing tissue sensitivity to insulin (biguanides, thiazolidinediones), or by slowing postprandial intestinal glucose absorption (alpha-glucosidase inhibitors).
Other antihyperglycaemic approaches have been contemplated for treating diabetes and high blood sugar, including inhibition of the renal sodium-dependent glucose cotransporter SGLT2. SGLT2 in the kidney regulates glucose levels by mediating the reabsorption of glucose back into the plasma following filtration of the blood. SGLT2 inhibition thus induces glucosuria and may reduce blood glucose levels.
SGLT2 inhibition has not previously been contemplated for use in equine animals, in particular in insulin-resistant equine animals. In equine animals, insulin-resistance, i.e. failure of tissues to respond appropriately to insulin, generally becomes manifest as hyperinsulinaemia. When insulin-resistant target tissues, e.g. skeletal muscle, have a reduced capacity for glucose uptake, the pancreas is stimulated to release more insulin, leading to hyperinsulinaemia. Insulin-resistant equine animals, e.g. horses, do not appear to have high blood glucose. For that reason, it would appear to be counter-intuitive to apply an approach that reduces blood glucose by transferring glucose out of the blood into the urine, even if this was previously known in a context of high blood glucose.
Further prior art is as follows:
U.S. Pat. No. 3,732,231 deals with D-6-methyl-8-cyano-methylergoline and a method of making the same, wherein the therein disclosed compounds constitute antifertility and lactation inhibiting agents.
U.S. Pat. No. 3,901,894 relates to 8-thiomethylergolines useful as prolactin inhibitors.
U.S. Pat. No. 3,920,664 is directed to D-2-halo-6-alkyl-8-substituted ergolines and related compounds that function as prolactin inhibitors.
U.S. Pat. No. 3,959,288 discloses 8-oxymethylergolines and a process of making the same, wherein the therein disclosed compounds constitute prolactin inhibitors.
EP 0 003 667 and U.S. Pat. No. 4,166,182 describe substituted ergolines, their preparation, compositions containing them and their use as pharmaceuticals, e.g. for the inhibition of prolactin secretion or the treatment of Parkinson's syndrome.
EP 0 026 671 and U.S. Pat. No. 4,246,265 deals with D-6-n-propylergoline derivatives compositions containing them and their use as pharmaceuticals, e.g. for lowering the prolactin levels in mammals or for treating symptoms of Parkinson's syndrome in humans.
EP 0 213 850 and U.S. Pat. No. 4,782,152 relates to a process for the decyanation of pergolide intermediate.
WO 96/40139 is directed to novel formulations for the transdermal delivery of pergolide.
WO 02/11727 discloses a formulation and a method of manufacturing stable pergolide mesylate.
WO 2007/129053 describes methods of diagnosis and treatment of equine laminitis and Cushing's syndrome.
The objective underlying the present invention is therefore to provide a medication for preventing and/or treating metabolic disorders in equine animals, which overcomes the problems of the prior art.